Saturday, 29 March 2014

Inflaming inflammation and psychiatry

The systematic review published by Mitchell & Goldstein [1] kinda says it all when it comes to our current view of the topic of inflammation and psychiatry, and in particular inflammation and neuropsychiatric conditions such as autism, schizophrenia and attention deficit hyperactivity disorder (ADHD): "There is preliminary evidence for elevated markers of inflammation in this population".
All at sea (JMW Turner) @ Wikipedia 

I've talked quite a bit on this blog about how, as strange as it might seem, heightened inflammation and inflammatory processes/markers do seem to be over-represented in a fair few diagnoses with a neuropsychiatric element to them (see here and see here for example). Granted, one has to be careful not to over-generalise to an entire population (remember: autisms not autism) and the chicken-and-egg question of which came first inflammation or condition still hangs over this 'association.' But the realisation that inflammatory processes may link immune function to behavioural presentation [2] is not to be sniffed at and may yet offer some intriguing new avenues for things like intervention [3].

The Mitchell / Goldstein review very sensibly notes that: "the data are inconsistent" and sound the oft-heard call for "Larger, prospective studies [which] are needed to realize the goal of inflammatory markers informing clinical practice". But, there is not escaping that immune function may be doing so much more than just protecting us for the myriad of beasties which wish to either call us home or make a meal of us or both.

As if to further prove the point, I also chanced on the study by Charity Onore and colleagues [4] who alongside some notable names on the autism research scene looked at the concept of maternal immune activation on the inflammatory status of offspring. The name Charity Onore has (again!) been talked about on this blog and some particularly interesting work looking at adhesion molecules and autism (see here); an area which has since been followed up (see here). The focus on the concept of the maternal immune activation (MIA) model is nothing new when it comes to autism research for example (see here and see here) denoting how elevated inflammatory responses at certain critical times during the nine months that made us may have some important consequences for offspring.

The latest Onore paper details how in a mouse model of MIA (based on the artificial stimulation of mother mice using poly I:C as the immunostimulating agent) "macrophage cytokine production in adult offspring" was the experimental target. Macrophages, also known as the 'big eaters' of the immune system, represent an important part of immune function undertaking some important tasks. Again, they have been mentioned in other blog entries, notably with the initial chatter about GcMAF in connection to autism (see here).

Anyhow, based on the MIA model, Onore et al  reported that analysis of adult offspring mice samples ("femurs were collected and bone marrow-derived macrophages were generated") for the presence of various cytokines with or without conditions of stimulation (LPS... see here) produced some interesting results. So for example, "a higher production of CCL3", a chemokine, was recorded. Indeed, elevations in CCL3 otherwise known as MIP-1α, was recorded both with and without stimulation leading authors to conclude: "a general increase in production of this chemokine". Their closing remark on their cumulative results being: "Collectively, these data suggest that MIA can produce lasting changes in macrophage function that are sustained into adulthood". I should add 'in mice' to the end of that sentence too.

Whilst there is still much to do in this potentially important area of research, what I perhaps would like readers to take from this post are a few things: (i) inflammation and by inference, immune system involvement, is an emerging area when it comes to behaviour and development, and (ii) whilst not ruling out the suggestion that there may be a variable genetic fragility to various neurodevelopmental conditions (perhaps even overlapping common ground) one would be wise to look at the interaction with our environment [5] as being an equally important variable [6] particularly during our earliest days of being. Oh, and that inflammation or inflammatory processes might be relevant to other tissues outside of just the grey-pinkish matter floating in the skull...

Music to close. Having seen the brilliant Franz Ferdinand play live this week, I'd refer you to perhaps their most famous song: Take me out. Or if you prefer, the live version from the venue on Thursday noting that this is not my own recording...


[1] Mitchell RH. & Goldstein BI. Inflammation in Children and Adolescents With Neuropsychiatric Disorders: A Systematic Review. J Am Acad Child Adolesc Psychiatry. 2014 Mar;53(3):274-296.

[2] Sommer IE. et al. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014 Jan;40(1):181-91.

[3] Dada T. et al. Mouse model of intrauterine inflammation: Sex-specific differences in long-term neurologic and immune sequelae. Brain Behav Immun. 2014 Jan 31. pii: S0889-1591(14)00015-4.

[4] Onore CE. et al. Maternal Immune Activation Leads to Activated Inflammatory Macrophages in Offspring. Brain Behav Immun. 2014 Feb 21. pii: S0889-1591(14)00053-1.

[5] Meyer U. Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry. 2014 Feb 15;75(4):307-15.

[6] Goyal DK. & Miyan JA. Neuro-Immune Abnormalities in Autism and Their Relationship with the Environment: A Variable Insult Model for Autism. Front Endocrinol (Lausanne). 2014 Mar 7;5:29.

---------- Mitchell RH, & Goldstein BI (2014). Inflammation in Children and Adolescents With Neuropsychiatric Disorders: A Systematic Review. Journal of the American Academy of Child and Adolescent Psychiatry, 53 (3), 274-296 PMID: 24565356 Onore CE, Schwartzer JJ, Careaga M, Berman RF, & Ashwood P (2014). Maternal Immune Activation Leads to Activated Inflammatory Macrophages in Offspring. Brain, behavior, and immunity PMID: 24566386